Use of External Controls in Regulatory Decision-Making.

The expanded use of electronic data retrieval systems has greatly expanded the potential sources of real-world data and presents new opportunities for evidence generation outside of the traditional research trial. These data may be used to inform trial design and interpretation as well. Externally controlled trials, such as single-arm and noninferiority designs, have long been used in regulatory decision-making despite the potential flaws based on assumptions of assay sensitivity and constancy.

Computational models for detection of endocrinopathy in subfertile males.

The observation that men with sperm density greater than 10 million/ml had low probability of endocrinopathy led to a refinement in the evaluation of subfertility. Using statistical methods, we sought to provide a more accurate prediction of which patients have an endocrinopathy, and to report the outcome as the odds of having disease. In addition, by examining the parameters that influenced the model significantly, the underlying pathophysiology might be better understood. Records of 1035 men containing variables including testis volume, sperm density, motility as well as the presence of endocrinopathy were randomized into 'training' and 'test' data sets. We modeled the data set using linear and quadratic discriminant function analysis, logistic regression (LR) and a neural network. Wilk's regression analysis was performed to determine which variables influenced the model significantly. Of the four models investigated, LR and a neural network performed the best with receiver operating characteristic areas under the curve of 0.93 and 0.95, respectively, correlating to a sensitivity of 28% and a specificity of 99% for the LR model, and a sensitivity and specificity of 56 and 97% for the neural network model. Reverse regression yielded P-values for the testis volume and sperm density of <0.0001. The neural network and LR models accurately predicted the probability of an endocrinopathy from testis volume, sperm density and motility without serum assays. These models may be accessed via the Internet, allowing urologists to select patients for endocrinologic evaluation at http://www.urocomp.org.

Successful management of infertility due to retrograde ejaculation using assisted reproductive technologies: a report of two cases.

Although retrograde ejaculation is a relatively uncommon cause of infertility, it is nonetheless the most common cause of ejaculatory dysfunction. Retrograde ejaculation is characterized by either all or part of the seminal fluid going into the bladder. The initial management of patients with ejaculatory dysfunction is medical therapy. In couples who have failed medical therapy, assisted reproductive techniques using sperm harvested from either the urine or the male reproductive tract would be the ultimate option. We report successful management of two couples, both men with advanced age and complete retrograde ejaculation, by intrauterine insemination in one and in vitro fertilization (IVF) using intracytoplasmic sperm injection (ICSI) in the other using sperm harvested from urine. The cases reported herein suggest that male infertility due to retrograde ejaculation may be successfully treated in men significantly older than the usual reproductive age and that traditional methods of hydration and urine alkalinization allow for the successful recovery of fertile sperm for ART. The selection of the method of ART must be individualized to the needs of each couple based upon both male and female factors.

Assessment of the androgen environment within the human testis: minimally invasive method to obtain intratesticular fluid.

Previous studies of the rat have shown that testosterone concentrations within the interstitial and seminiferous tubularfluids of the testes are significantly higher than normal serum levels, and further, that although intratesticular testosterone concentration can be substantially reduced without an effect on spermatogenesis, the concentration that is minimally required to maintain spermatogenesis is also substantially higher than serum levels. The purpose of the present study was to adapt a minimally invasive technique to sample human intratesticular fluid to enable parallel observations in man. To this end, aspiration methods were first developed for the rat testis and then adapted to the human. The testosterone concentration in fluid obtained by unilateral aspiration of rat testes was approximately 50 ng/mL, similar to the known concentration in seminiferous tubular fluid. These aspiration methods were then adapted to obtain intratesticular fluid from human testes. Studies of 12 fertile human subjects demonstrated that percutaneous testicular aspiration could be performed safely and successfully using a 19-gauge needle. Nine additional human subjects had bilateral testicular aspiration and simultaneous measurement of peripheral blood testosterone levels. Testicular aspirations yielded 8 to 117 microL of fluid from each testicle. The mean concentration of testosterone in aspirates obtained from the 21 patients was 609 +/- 50 ng/mL. Dihydrotestosterone and 3alpha-androstanediol concentrations were quite low, below the limits of detection of our assay. The SHBG/ABP concentration in the aspirates was 8.5 +/- 1.1 nM. These results define testosterone as the major androgenic steroid in the human testis, as in the rat testis, and indicate that the testosterone concentration within the human testis is approximately 200-fold greater than that of SHBG/ABP, and more than 100-fold greater than the concentration of testosterone found in normal human serum.

Effects of varicocele on male fertility.

Varicoceles are vascular lesions of the pampiniform plexus and are the most common identifiable abnormality found in men being evaluated for infertility. Despite the long history associated with varicoceles, there remains much controversy regarding their diagnosis and management. The purpose of this manuscript is to address three of the most pressing controversies: (i) the association of varicoceles with male infertility, (ii) whether varicoceles exert a progressive deleterious effect and (iii) the relationship of varicocele size and outcome following varicocele repair. The current literature is reviewed in an effort to answer these questions. Based upon this analysis, conclusions can be drawn regarding the best management of varicoceles in subfertile men, adolescents, young fertile men and men with subclinical varicoceles. Although there remain many controversies due to a paucity of data, there appears to be a significant difference between adults and adolescents with respect to a progressive deterioration of semen parameters and it is clear that subclinical varicoceles do not play a major role in male infertility.

Puboprostatic ligament sparing radical retropubic prostatectomy.

Prostate cancer is the most common solid malignancy and the second most common cause of cancer death in man. Radical prostatectomy is the therapeutic modality that currently provides the best long-term biochemical relapse-free survival rate. Yet many patients select alternative forms of therapy or no therapy at all because of fears that treatment will significantly alter quality of life. Urinary incontinence following radical prostatectomy has a significant deleterious effect on quality of life and, unfortunately, is much more prevalent following surgery compared with other treatment modalities, such as radiation therapy. Many efforts have been undertaken to avoid this complication with only modest success achieved. These include creation of a neobladder neck, bladder neck preservation, periurethral injection of bulking agents, and anterior urethropexy. A technique for radical retropubic prostatectomy that spares the puboprostatic ligaments, which preserves the normal anterior support of the urethra, is described herein. The outcome following this procedure demonstrates more rapid return of full urinary continence following radical prostatectomy in a controlled study. However, the "Holy Grail" of complete eradication of urinary incontinence following radical prostatectomy has not been achieved.

Seminal vesicle aspiration in spinal cord injured men: insight into poor sperm quality.

PURPOSE: In men with spinal cord injury poor quality semen is seen when performing electroejaculation and penile vibratory stimulation. We determined whether sperm stasis within the seminal vesicles is a potential cause of this problem. MATERIALS AND METHODS: Seminal vesicle aspiration was performed immediately before electroejaculation or penile vibratory stimulation in men with aspermia secondary to spinal cord injury. Sperm count and quality of seminal vesicle aspiration and subsequent ejaculation were compared with historical ejaculated counts, ultrasound findings and patient characteristics. RESULTS: Mean total number of right plus left seminal vesicle sperm plus or minus standard deviation was 511 +/- 960 x 10(6). Mean total number of sperm obtained by seminal vesicle plus electroejaculation or penile vibratory stimulation was 918 +/- 1,261 x 10(6). Average motility and viability of the seminal vesicle aspirated sperm were 1.3 and 3.2%, respectively. Average motility of the ejaculated sperm was 26.4% after seminal vesicle aspiration versus 16.3% in previous ejaculation induction procedures performed in the same patients. Seminal vesicle aspirated sperm represented 66% of the total number of sperm obtained during the session and was equal to 49% of the sperm obtained at previous electroejaculation or penile vibratory stimulation sessions. The period of abstinence correlated only with ejaculate count (simple regression p = 0.009). No other clinical characteristics had any effect on sperm count or quality. CONCLUSIONS: Large numbers of poor quality sperm are present within the seminal vesicles of spinal cord injured men and these sperm comprise a large portion of the specimens collected by electroejaculation or penile vibratory stimulation. This phenomenon is independent of the period of abstinence, implicating disordered storage of sperm due to spinal cord injury rather than infrequent ejaculation. The large number of senescent sperm within the seminal vesicles appears to be a primary cause of poor sperm quality in spinal cord injured men.

Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men.

PURPOSE: Finasteride, an oral type 2, 5alpha-reductase inhibitor, is used in 1 mg. daily doses for the treatment of male pattern hair loss. A dose of 5 mg. finasteride daily reduces ejaculate volume by approximately 25%, and reduces prostate volume by approximately 20% and serum prostate specific antigen (PSA) by approximately 50% in men with benign prostatic hyperplasia. To our knowledge no data exist on the effect of 1 mg. finasteride daily on ejaculate volume or other semen parameters, or on the prostate in young men. Therefore, we studied the potential effect and reversibility of effect of 1 mg. finasteride daily on spermatogenesis, semen production, the prostate and serum PSA in young men. MATERIALS AND METHODS: In this double-blind, placebo controlled multicenter study 181 men 19 to 41 years old were randomized to receive 1 mg. finasteride or placebo for 48 weeks followed by a 60-week off-drug period. Of the 181 men 79 were included in a subset for the collection and analysis of sequential semen samples. RESULTS: There were no significant effects of 1 mg. finasteride on sperm concentration, total sperm per ejaculate, sperm motility or morphology. Ejaculate volume in subjects on finasteride decreased 0.3 ml. (-11%) compared to a decrease of 0.2 ml. (-8%) for placebo, with a median between treatment group difference of -0.03 ml. (1%, 90% confidence interval -10.4 to 13.1, p = 0.915). There were significant but small decreases in prostate volume (-2.6%) and serum PSA (-0.2 ng./ml.) in the finasteride group, which reversed on discontinuation of the drug. CONCLUSIONS: Treatment with 1 mg. finasteride daily for 48 weeks did not affect spermatogenesis or semen production in young men. The effects of 1 mg. finasteride daily on prostate volume and serum PSA in young men without benign prostatic hyperplasia were small and reversible on discontinuation of the drug.

Clinical efficacy of sildenafil citrate based on etiology and response to prior treatment.

PURPOSE: We assess the clinical efficacy of sildenafil citrate and predictors of satisfactory outcome. MATERIALS AND METHODS: All patients treated with sildenafil citrate within the first 6 weeks of its release were evaluated with a self-administered questionnaire before and at completion of therapy to assess etiology of erectile dysfunction, level of sexual function, libido, response to previous therapies, response to therapy with sildenafil citrate and quality of life. Sexual function was measured before and during therapy using an abbreviated version of the International Index of Erectile Function, with a successful outcome defined as a level of satisfaction of 4 or 5 on a 5-point scale. RESULTS: Followup was obtained in 267 of the 308 patients who entered the study. Mean age plus or minus standard deviation was 61+/-9.6 years and duration of erectile dysfunction was 4.1+/-3 years. Overall satisfaction with sildenafil citrate for the entire patient population was 65% and response to prior therapies did not affect satisfaction. There was a significant positive correlation between baseline sexual function and response to sildenafil citrate but even patients with severe erectile dysfunction had a 41% satisfaction rate. Etiology of erectile dysfunction had a significant impact on satisfaction rate, with neurogenic causes of erectile dysfunction (diabetes, prostate surgery and so forth) having significantly lower rates than psychogenic or vasculogenic erectile dysfunction. CONCLUSIONS: Sildenafil citrate is a highly effective oral agent for the treatment of erectile dysfunction in clinical practice. The best predictors for response to sildenafil citrate therapy are baseline sexual function and etiology of erectile dysfunction. However, we could not identify any patient characteristic that would predict absolute failure for sildenafil citrate therapy. Therefore, all patients with erectile dysfunction who do not have specific contraindications should be considered for sildenafil citrate therapy.

Unilateral obstruction of the vas deferens diagnosed by seminal vesicle aspiration.

Causes of vasal obstruction include vasectomy, inguinal surgery, scrotal surgery, and congenital anomalies. The incidence of unilateral obstruction in various clinical situations is unknown because sperm from the contralateral testicle usually is present in the ejaculate. Vasography is the standard technique used to diagnose a unilateral vas deferens obstruction. We used the technique of seminal vesicle aspiration to accurately diagnose unilateral vas deferens obstruction in a man who had a previous inguinal hernia repaired with mesh. Surgical exploration confirmed the impression of vasal obstruction, and successful vasovasostomy was performed. We believe that seminal vesicle aspiration may be helpful in the diagnosis of unilateral vas deferens obstruction and has potential benefits over vasography.

Erectile dysfunction and sildenafil citrate and cardiologists.

Since the release of sildenafil citrate (Viagra), increasing numbers of patients are seeking treatment for erectile dysfunction (ED). Many of the risk factors for ED are the same as those for cardiac disease. Sildenafil citrate is a highly effective oral agent for ED. It is absolutely contraindicated in patients receiving organic nitrates. The issue of cardiac deaths associated with sildenafil citrate and ways of potentially minimizing these cases are discussed.

Puboprostatic ligament sparing improves urinary continence after radical retropubic prostatectomy.

OBJECTIVES: To determine whether a puboprostatic ligament-sparing technique of prostatic apical dissection provided improved urinary continence after radical retropubic prostatectomy. METHODS: A total of 43 men with clinically localized prostate cancer underwent radical retropubic prostatectomy (standard apical dissection in 25, puboprostatic ligament-sparing technique in 18). Patients were evaluated by independent observer questionnaire to determine their continence status. The questionnaire was tested in a control group of 25 men who had not undergone prostate surgery. The overall continence rate and time to achieve continence was compared between the two surgical groups. In addition, the clinical and pathologic stages and both the rate and location of positive margins were assessed. RESULTS: Mean patient age and serum prostate-specific antigen values were not significantly different between the two groups. Clinical and pathologic stages were also similar. The mean follow-up period for the puboprostatic ligament-sparing group was 35 weeks compared with 57 weeks for the standard group (P < 0.05). The median time until continence was achieved after surgery was significantly shorter (P = 0.01) for the puboprostatic ligament-sparing group than for the standard method (6.5 and 12 weeks, respectively). However, the overall continence rate at 1-year follow-up for the two groups was similar (100% and 94%, respectively). The positive margin rate and location of positive margins were not different with the puboprostatic ligament-sparing technique. CONCLUSIONS: The puboprostatic ligament-sparing technique improves the rapidity of return of urinary continence after radical prostatectomy without significantly enhancing overall continence or interfering with the therapeutic efficacy of the procedure.

Comparison of long-term outcomes of penile prostheses and intracavernosal injection therapy.

PURPOSE: Intracavernosal injection therapy is one of the most popular therapies for erectile dysfunction today. Yet, most clinicians consider intracavernosal injection a palliative treatment for erectile dysfunction because of the high patient initiated dropout rate. In contrast, penile prostheses appear to offer a more permanent cure for erectile dysfunction. We compare the long-term outcomes of both therapies in contemporaneously treated patients and determine the reasons for failure of each. MATERIALS AND METHODS: Telephone survey and chart review was conducted on the first 115 patients treated with intracavernosal injection and 65 patients undergoing insertion of a penile prosthesis during the same period at our institution. Mean patient age was 57 and 60 years, respectively, and mean followup of all patients was 5.4 years (range of 3.3 to 16). RESULTS: An equal percentage of patients were lost to followup in both groups, including 19% of the intracavernosal injection group and 18% of the penile prosthesis group. Of the intracavernosal injection patients 6 (6%) died during followup and 10 (19%) of the prosthetic patients died (p < 0.05). At the time of contact only 41% of the patients were still using intracavernosal injection. In contrast, 70% of the patients were still sexually active with the prosthesis (p < 0.01). Mean duration of use of the penile prosthetics was 63 months compared to 37 months for intracavernosal injection (p < 0.001). The most common reasons for discontinuing intracavernosal injection were inadequate erections (16 cases), lack of spontaneity (14), side effects (12), lack of partner (10), loss of sexual interest (6) and spontaneous return of normal erections (4). More than half of the patients (61%) who discontinued intracavernosal injection remain sexually active with other therapies, including penile prosthesis in 11, vacuum devices in 4, vascular surgery in 1 and oral medication in 1, and 14 without any therapy. We could not identify any significant clinical parameters that would accurately predict which patients most benefited by the long-term use of intracavernosal injection therapy. In contrast, only 6 patients discontinued use of the implant because of complications (infection, erosion and malfunction) and 7 for reasons independent of the implant (that is lack of partner, loss of sexual interest and co-morbidity). CONCLUSIONS: Intracavernosal injection serves as only a palliative therapy for the majority of patients with erectile dysfunction but there exists a core group who derives long-term satisfaction with its use. The majority of patients who discontinue intracavernosal injection remain sexually active yet do not progress to more invasive or effective therapies. The reason for discontinuing therapies for erectile dysfunction is often unrelated to the actual therapeutic modality. Our findings suggest that further improvements in intracavernosal injection therapy and the development of alternative methods of delivery of vasoactive agents will have only a limited impact on the overall outcome of therapy for erectile dysfunction and that increased attention to issues separate from the erection is warranted.

Endocrine evaluation of infertile men.

OBJECTIVES: To determine the incidence and type of endocrinologic abnormalities in men undergoing infertility evaluations and the most appropriate testing to detect them. METHODS: A retrospective review of consecutive patients attending two infertility centers was performed. Results of endocrine testing were compared to medical history and physical and laboratory findings to determine whether endocrinologic screening could be limited to a specific subpopulation. RESULTS: Only 99 of the 1035 patients (9.6%) had abnormal endocrine studies upon repetitive testing. The majority of these patients had an isolated elevation of serum follicle stimulating hormone (FSH) levels. Only 1.7% had a clinically significant endocrinopathy that would have had an effect upon disease management. Screening with serum testosterone and FSH levels alone was just as effective as a complete hormonal panel of testosterone, FSH, luteinizing hormone, and prolactin for the detection of clinically significant endocrinopathy. Only 1 patient with a clinically significant endocrinopathy would not have been identified if hormonal screening was limited to only those patients with a sperm density of less than 10 x 10(6)/mL. CONCLUSIONS: Endocrinopathies are a rare cause of male infertility. Endocrine screening of men with sperm counts of less than 10 million/mL with serum testosterone and FSH levels alone will detect the vast majority of clinically significant endocrinopathies.

Transrectal US-guided seminal vesiculography.

Transrectal ultrasound (US)-guided seminal vesiculography is a technique that couples US with radiography to evaluate male-factor infertility. Seminal vesiculography was performed in 12 patients after needle puncture of the seminal vesicle to inject contrast material for radiography. Seminal vesiculography helped imaging of the distal male reproductive tract (vas deferens, seminal vesicles, ejaculatory ducts). This method is an improvement over standard vasography for evaluation of infertility in men with suspected ejaculatory-duct obstruction.